6-{2-[1-(6-Methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is disclosed as Compound 35 in Applicant's earlier filed WO 2002/050045 (the '045 publication) and has the following general structure.

6-{2-[1-(6-Methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is also known by its international non-proprietary Name (INN) as “vapendavir”. Vapendavir is an antiviral agent which has been found, as previously described, to be particularly useful in the treatment and/or prevention of picornaviral infections such as human rhinovirus (HRV) and enteroviral infections as well as in the treatment and/or alleviation of symptoms of asthma and/or chronic obstructive pulmonary disease (COPD) and the reduction of the incidence of exacerbations and/or the prevention of exacerbations as asthma and/or COPD (see WO2002/050045, WO2011/127538 and WO2011/160191). Human rhinoviruses are a member of the genus Rhinovirus of the picomavirus family and are believed to be responsible for between 40 and 50% of common cold infections. Human rhinoviruses comprise a group of over 100 serotypically distinct viruses. Vapendavir has thus been shown to be effective against viruses of the Picornaviridae family which is also represented by the Enteroviruses. This genus includes polioviruses 1-3, coxsackieviruses A (23 serotypes) and B (6 serotypes), echoviruses (31 serotypes) and numbered enteroviruses 68-71. The clinical syndromes caused by enteroviruses include poliomyelitis, meningitis, encephalitis, pleurodynia, herpangina, hand foot and mouth disease, conjunctivitis, myocarditis and neonatal diseases such as respiratory illnesses and febrile illnesses. Viruses of the Picornavirus family are characterized by a single stranded (+) RNA genome encapsidated by a protein shell (or capsid) having pseudo icosahedral symmetry. The surface of the capsid contains “canyons” which surround each of the icosahedral fivefold axes, and it is believed that the cellular receptors bind to residues on the canyon floor.
One example in WO2002/050045, Example 6, describes the small-scale synthesis of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole via a Mitsunobu coupling using a polymer-supported triphenylphosphine reagent and isolation in milligram quantity as a white powder following gradient elution column chromatography (see Example 6, page 36).
WO 2009/143571 (the '571 PCT publication) discloses particularly preferred salt forms of vapendavir, including a bis-dihydrogenphosphate crystalline salt form of vapendavir which is described as having desirable solubility and/or stability properties. However, following large-scale drug product manufacture, the inventors have discovered that this desirable crystalline salt form of vapendavir bisphosphate suffers from a phenomenon known as “process induced transformation” or “water induced phase changes” whereby the production of a significant amount of at least one other crystalline phase such as sesquiphosphate semihydrate was observed. The inventors also discovered that the square-planar crystal habit of the bis-dihydrogenphosphate salt of vapendavir had poor flow properties and a propensity to form agglomerates during manufacturing that in combination prevented reproducible formulation of the active drug.
In the art of compound formulation, manufacturing specific crystalline forms of compounds is a difficult pursuit and there is much uncertainty regarding the manufacture of a predictable and repeatable crystalline form. For example, the article “From Form to Function: Crystallization of Active Pharmaceutical Ingredients” by Variankaval et al., AIChE Journal, Vol. 54, No. 7, 1682-1688 (2008), herein incorporated by reference, describes the challenges in preparing desirable (pharmaceutical or other formulation) crystallizations with desired formulation properties. Problems that have been difficult to overcome in this field include undesirable qualities or excessive variability with regard to crystal shape and size, particle size distribution, solubility, and numerous other physical attributes necessary for efficient and useful manufacture of crystal forms, particularly as it relates to large scale production. As indicated in the article, most techniques in this field are “far from ready to handle the complexity of drug molecules being crystallized from real process streams in large-scale equipment.” See Variankaval et al. at page 1687.
Even further, problems in stability in this field have made it difficult to come up with effective formulations that can be made into suspensions. Primarily with regard to the care of pediatric patients, suspensions are often a necessary avenue of treatment, but problems in developing an active ingredient of the proper stability and solubility has greatly limited the number of effective suspensions that can be prepared from the active ingredients.
In addition, there continues to be an unmet need for an anti-picornavirus compound that is particularly useful to treat and/or prevent infections including picornavirus infections such as those caused by human rhinovirus or enteroviruses and which is also safe and effective. Still further, there is a need to develop new pharmaceutical compositions that can readily be made into solid tablet form and other useful forms such as suspensions that can overcome previous problems with regard to manufacturing and repeatability such as uniform particle size necessary to ensure a safe and stable oral medication. Even further, there is a need for a new and useful form of medication which can be obtained in an efficient manufacturing process that can be used in large scale production while minimizing overall costs.
The present inventors have discovered an anhydrous, i.e. non-hydrate, crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole in its free base form, i.e. non-salt form, that is considered to possess one or more advantages including, for example, allowing for a more stable, efficient and less expensive large-scale manufacture of pharmaceutical compositions comprising 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. In addition, the inventors have developed useful formulations for delivering the active ingredient, including tablets, capsules, suspensions and other forms.